Cambridge was born in New York City to parents who were immigrants from British Guiana. He began school in Nova Scotia while living with his grandparents, but returned to New York City and graduated from Flushing High School. He then studied at Hofstra College, where he became interested in acting.
Cambridge appeared both on stage and screen. Memorable film roles include Watermelon Man, where he plays the lead character, a white bigot who one day wakes up and discovers his skin color has turned to black, and The President's Analyst, where he plays a depressed government agent. He also had a starring role in the 1970 Ossie Davis adaptation of the Chester Himes novel Cotton Comes to Harlem of the same name. He perhaps reached his largest audience in a series of comical television commercials for Jockey brand underwear.
Cambridge is also remembered for his starring role in Beware! The Blob, a sequel to the The Blob, as well as appearances on several syndicated television programs, including Car 54 Where Are You? ("The Curse of the Snitkins"), The Dick Van Dyke Show ("The Man From My Uncle"), and I Spy ("Court of the Lion").
He had a number of starring theatrical roles, both on and off Broadway, including his Broadway debut in Nature's Way (1951). He later appeared in The Blacks, in a performance that earned him an Obie award in 1961. He also did a stock version of A Funny Thing Happened on the Way to the Forum four years later.
In addition to acting, Cambridge was a well-known standup comedian who appeared on The Tonight Show and other television shows. His routines were imbued with biting sarcasm and trenchant topical humor that was common in comedic circles at the time.
Godfrey Cambridge died of a heart attack at the age of 43 while on the set of the movie Victory at Entebbe, in which he was to portray Idi Amin. Amin claimed Cambridge's death was "punishment from God." It is possible the frequently overweight Cambridge's habit of yo-yo dieting contributed to his early demise, as his death was preceded by a rapid weight loss.